The Interaction Between NF-κB and Estrogen in Alzheimer's Disease.

Post-menopausal women are at a higher risk of developing Alzheimer's disease (AD) than males. The higher rates of AD in women are associated with the sharp decline in the estrogen levels after menopause. Estrogen has been shown to downregulate inflammatory cytokines in the central nervous system (CNS), which has a neuroprotective role against neurodegenerative diseases including AD. Sustained neuroinflammation is associated with neurodegeneration and contributes to AD. Nuclear factor kappa-B (NF-κB) is a transcription factor involved with the modulation of inflammation and interacts with estrogen to influence the progression of AD. Application of 17ß-estradiol (E2) has been shown to inhibit NF-κB, thereby reducing transcription of NF-κB target genes. Despite accumulating evidence showing that estrogens have beneficial effects in pre-clinical AD studies, there are mixed results with hormone replacement therapy in clinical trials. Furthering our understanding of how NF-κB interacts with estrogen and alters the progression of neurodegenerative disorders including AD, should be beneficial and result in the development of novel therapeutics.

Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer's Disease.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer's disease (AD). The classic hallmarks of AD include ß-amyloid (Aß) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD.

The Effect of COVID-19 on NF-κB and Neurological Manifestations of Disease.

The coronavirus disease that presumably began in 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic. Initially, COVID-19 was thought to only affect respiration. However, accumulating evidence shows a wide range of neurological symptoms are also associated with COVID-19, such as anosmia/ageusia, headaches, seizures, demyelination, mental confusion, delirium, and coma. Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients.

Potential New Approaches for Diagnosis of Alzheimer's Disease and Related Dementias.

Dementia is an umbrella term-caused by a large number of specific diagnoses, including several neurodegenerative disorders. Alzheimer's disease (AD) is now the most common cause of dementia in advanced countries, while dementia due to neurosyphilis was the leading cause a century ago. Many challenges remain for diagnosing dementia definitively. Some of these include variability of early symptoms and overlap with similar disorders, as well as the possibility of combined, or mixed, etiologies in some cases. Newer technologies, including the incorporation of PET neuroimaging and other biomarkers (genomics and proteomics), are being incorporated into revised diagnostic criteria. However, the application of novel diagnostic methods at clinical sites is plagued by many caveats including availability and access. This review surveys new diagnostic methods as well as remaining challenges-for clinical care and clinical research.

Interactions between medial prefrontal cortex and dorsomedial striatum are necessary for odor span capacity in rats: role of GluN2B-containing NMDA receptors.

Working memory is involved in the maintenance and manipulation of information essential for complex cognition. While the neural substrates underlying working memory capacity have been studied in humans, considerably less is known about the circuitry mediating working memory capacity in rodents. Therefore, the present experiments tested the involvement of medial prefrontal cortex (mPFC) and dorsal striatum (STR) in the odor span task (OST), a task proposed to assay working memory capacity in rodents. Initially, Long Evans rats were trained to dig in scented sand for food following a serial delayed nonmatching-to-sample rule. Temporary inactivation of dorsomedial (dm) STR significantly reduced span in well trained rats. Inactivation of mPFC or contralateral disconnection of the mPFC and dmSTR also reduced span. Infusing the GluN2B-containing NMDA receptor antagonist Ro 25-6981 into mPFC did not affect span; however, span was significantly reduced following bilateral Ro 25-6981 infusions into dmSTR or contralateral disconnection of mPFC (inactivation) and dmSTR (Ro 25-6981). These results suggest that span capacity in rats depends on GluN2B-containing NMDA receptor-dependent interactions between the mPFC and the dmSTR. Therefore, interventions targeting this circuit may improve the working memory capacity impairments in patients with schizophrenia, Alzheimer's disease, and Parkinson's disease.

Medial prefrontal cortex and dorsomedial striatum are necessary for the trial-unique, delayed nonmatching-to-location (TUNL) task in rats: role of NMDA receptors.

The trial-unique, delayed nonmatching-to-location (TUNL) task is a recently developed behavioral task that measures spatial working memory and a form of pattern separation in touchscreen-equipped operant conditioning chambers. Limited information exists regarding the neurotransmitters and neural substrates involved in the task. The present experiments tested the effects of systemic and intracranial injections of NMDA receptor antagonists on the TUNL task. After training, male Long Evans rats systemically injected with the competitive NMDA receptor antagonist CPP (10 mg/kg) had impaired accuracy regardless of the degree of stimuli separation or length of delay between the sample and test phases. Injections of Ro 25-6981 (6 or 10 mg/kg), an antagonist selective for GluN2B subunit-containing NMDA receptors, did not affect accuracy on the task. Direct infusion of the competitive NMDA receptor antagonist AP5 into mPFC or dmSTR reduced overall accuracy on the TUNL task. These results demonstrate that TUNL task performance depends on NMDA receptors within the mPFC and dmSTR.

Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring.

Maternal immune activation during pregnancy is an environmental risk factor for psychiatric illnesses such as schizophrenia in the offspring. Patients with schizophrenia display an array of cognitive symptoms, including impaired working memory capacity. Rodent models have been developed to understand the relationship between maternal immune activation and the cognitive symptoms of schizophrenia. The present experiment was designed to test whether maternal immune activation with the viral mimetic polyinosinic:polycytidylic acid (polyI:C) during pregnancy affects working memory capacity of the offspring. Pregnant Long Evans rats were treated with either saline or polyI:C (4mg/kg; i.v.) on gestational day 15. Male offspring of the litters (2-3months of age) were subsequently trained on a nonmatching-to-sample task with odors. After a criterion was met, the rats were tested on the odor span task, which requires rats to remember an increasing span of different odors to receive food reward. Rats were tested using delays of approximately 40s during the acquisition of the task. Importantly, polyI:C- and saline-treated offspring did not differ in performance of the nonmatching-to-sample task suggesting that both groups could perform a relatively simple working memory task. In contrast, polyI:C-treated offspring had reduced span capacity in the middle and late phases of odor span task acquisition. After task acquisition, the rats were tested using the 40s delay and a 10min delay. Both groups showed a delay-dependent decrease in span, although the polyI:C-treated offspring had significantly lower spans regardless of delay. Our results support the validity of the maternal immune activation model for studying the cognitive symptoms of neurodevelopmental disorders such as schizophrenia.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside.

RATIONALE: The cognitive symptoms observed in schizophrenia are not consistently alleviated by conventional antipsychotics. Following a recent pilot study, sodium nitroprusside (SNP) has been identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients. OBJECTIVE: The present experiments were designed to explore the effects of SNP on the highly translatable trial-unique, delayed nonmatching-to-location (TUNL) task in rats with and without acute MK-801 treatment. METHODS: SNP (0.5, 1.0, 2.0, 4.0, and 5.0 mg/kg) and MK-801 (0.05, 0.075, and 0.1 mg/kg) were acutely administered to rats trained on the TUNL task. RESULTS: Acute MK-801 treatment impaired TUNL task accuracy. Administration of SNP (2.0 mg/kg) with MK-801 (0.1 mg/kg) failed to rescue performance on TUNL. SNP (5.0 mg/kg) administration nearly 4 h prior to MK-801 (0.05 mg/kg) treatment had no preventative effect on performance impairments. SNP (2.0 mg/kg) improved performance on a subset of trials. CONCLUSION: These results suggest that SNP may possess intrinsic cognitive-enhancing properties but is unable to block the effects of acute MK-801 treatment on the TUNL task. These results are inconsistent with the effectiveness of SNP as an adjunct therapy for working memory impairments in schizophrenia patients. Future studies in rodents that assess SNP as an adjunct therapy will be valuable in understanding the mechanisms underlying the effectiveness of SNP as a treatment for schizophrenia.

Alterations in reward, fear and safety cue discrimination after inactivation of the rat prelimbic and infralimbic cortices.

Accurate discrimination of environmental cues predicting reward, fear, or safety is important for survival. The prelimbic and infralimbic cortices are implicated in regulating reward-seeking and fear behaviors; however, no studies have examined their roles in discriminating among reward, fear, and safety cues. Using a discriminative conditioning task that includes presentations of a reward cue (paired with a reward pellet), fear cue (paired with footshock), and a compound fear+safety cue (no footshock) within the same sessions allowed us to assess the flexibility and precision of fear and reward-seeking behaviors to these cues. We found that fear behavior was appropriately limited to the fear cue in untreated rats, but during infralimbic cortical inactivation, similar levels of fear were seen to the fear and compound fear+safety cues. Reward-seeking behavior was also appropriately limited to the reward cue in untreated rats. Inactivating the prelimbic cortex altered discriminative reward seeking as rats with prelimbic inactivation did not increase their reward seeking behavior during the reward cue to the same degree as saline controls. Our results imply dissociable roles of the two cortical regions: the prelimbic cortex in precise discriminative reward seeking and the infralimbic cortex in discriminating between fear and safety cues. These data suggest that alterations in the balance of activity between areas homologous to the prelimbic and infralimbic cortices may be involved in the processes that go awry in anxiety and addiction disorders.

GluN2B-containing NMDA receptors and AMPA receptors in medial prefrontal cortex are necessary for odor span in rats.

Working memory is a type of short-term memory involved in the maintenance and manipulation of information essential for complex cognition. While memory span capacity has been extensively studied in humans as a measure of working memory, it has received considerably less attention in rodents. Our aim was to examine the role of the N-methyl-D-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in odor span capacity using systemic injections or infusions of receptor antagonists into the medial prefrontal cortex (mPFC). Long Evans rats were trained on a well-characterized odor span task (OST). Initially, rats were trained to dig for a food reward in sand followed by training on a non-match to sample discrimination using sand scented with household spices. The rats were then required to perform a serial delayed non-match to sample procedure which was their odor span. Systemic injection of the broad spectrum NMDA receptor antagonist 3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) (10 mg/kg) or the GluN2B-selective antagonist Ro 25-6981 (10 mg/kg but not 6 mg/kg) significantly reduced odor span capacity. Infusions of the GluN2B- selective antagonist Ro 25-6981 (2.5 µg/hemisphere) into mPFC reduced span capacity, an effect that was nearly significant (p = 0.069). Infusions of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (1.25 µg/hemisphere) into mPFC reduced span capacity and latency for the rats to make a choice in the task. These results demonstrate span capacity in rats depends on ionotropic glutamate receptor activation in the mPFC. Further understanding of the circuitry underlying span capacity may aid in the novel therapeutic drug development for persons with working memory impairments as a result of disorders such as schizophrenia and Alzheimer's disease.

Inactivation of medial prefrontal cortex or acute stress impairs odor span in rats.

The capacity of working memory is limited and is altered in brain disorders including schizophrenia. In rodent working memory tasks, capacity is typically not measured (at least not explicitly). One task that does measure working memory capacity is the odor span task (OST) developed by Dudchenko and colleagues. In separate experiments, the effects of medial prefrontal cortex (mPFC) inactivation or acute stress on the OST were assessed in rats. Inactivation of the mPFC profoundly impaired odor span without affecting olfactory sensitivity. Acute stress also significantly reduced odor span. These findings support a potential role of the OST in developing novel therapeutics for disorders characterized by impaired working memory capacity.